Pancreatic Neuroendocrine Neoplasms Larger than 4 cm: A Retrospective Observational Study of Surgery, Histology, and Outcome.

BACKGROUND: Pancreatic neuroendocrine neoplasms (pNENs) are often detected as large primary lesions, even with distant metastases, and their prognosis may be difficult to predict. METHODS: In this retrospective study, we retrieved data of patients treated for a large pNEN in our Surgical Unit (1979-2017) to evaluate the possible prognostic role of clinic-pathological features and surgery. Cox-proportional hazard regression models were used to find possible associations among some variables (clinical features, surgery, and histology) and survival at univariate and multivariate analyses. RESULTS: Among 333 pNENs, we identified 64 patients (19%) with a lesion > 4 cm. Patients' median age was 61 years, median tumor size was 6.0 cm, and 35 (55%) patients had distant metastases at diagnosis. There were 50 (78%) nonfunctioning pNENs, and 31 tumors localized in the body/tail region of the pancreas. Overall, 36 patients underwent a standard pancreatic resection (with 13 associated liver resection/ablation). Regarding histology, 67% of pNENs were N1, and 34% were grade 2. After a median follow-up of 48 months (up to 33 years), 42 patients died of disease. Median survival after surgery was 79 months, and six patients experienced recurrence (median DFS 94 months). At multivariate analysis, distant metastases were associated with a worse outcome, while having undergone radical tumor resection was a protective factor. CONCLUSIONS: In our experience, about 20% of pNENs have a size > 4 cm, 78% are nonfunctioning, and 55% show distant metastases at diagnosis. Nevertheless, a long-term survival of more than five years may be achieved after surgery.

Pancreatic solid pseudopapillary neoplasm in male patients: systematic review with three new cases.

Pancreatic solid pseudopapillary neoplasm (pSPN) is a rare exocrine neoplasm, which generally occurs in young women. This study analyses the clinical characteristics of pSPN in male patients through a systematic review of the literature, adding three new cases from our institution. We reviewed our experience in Pspns, and we performed a systematic review of pSPN of all articles published in English in PubMed and SCOPUS from 1980. Using the final included articles, we evaluated clinic-pathological features, surgical treatment and prognosis of male patients affected by pSPN. From the literature review and our cases, we collected 246 male patients with a proven pSPN. Mean age was 34.3 (range 4-78) years, with 26.2% patients younger than 18 years. Patients were asymptomatic in 35.9% of cases, despite a mean tumour size of 6.3 cm. In 63.7% of cases, the pSPN was located in the body-tail region. Distant metastases were reported at diagnosis in only 10 (4.1%) patients. A correct pre-operative diagnosis (including cytopathology) was provided in 53.6% of patients, with only 40 fine-needle aspiration/biopsy performed. Standard pancreatic resections represented 90.4% of surgical procedures. Beta-catenin and progesterone receptors were positive at immunostaining in 100% and 77.8% of cases, respectively. Fourteen (7.2%) patients relapsed after a mean disease-free survival of 43.1 months. After a mean follow-up of 47 (range 4-180) months, 89.5% of patients were alive and disease-free. Although rare, when dealing with a solid-cystic pancreatic mass, even in asymptomatic male patients, a pSPN should be considered as a possible diagnosis.

A Plea for Surgery in Pancreatic Metastases from Renal Cell Carcinoma: Indications and Outcome from a Multicenter Surgical Experience.

BACKGROUND: Pancreatic metastases from renal-cell carcinoma (RCC-PMs) are rare. Surgery may play a role in improving overall (OS) and disease-free survival (DFS). METHODS: Clinical-pathological features, surgery and follow-up data of patients with RCC-PMs operated on in three pancreatic surgical centers (2000-2019) were retrospectively evaluated. RESULTS: Thirty-nine patients (21 male/18 female, averaging 65 years) were enrolled. RCC-PMs were metachronous in 36 patients (mean 94 months, up to 24 years after nephrectomy), multiple in 21 patients, and with a median size of 2.5 (range, 0.7-7.5) cm. All the patients underwent pancreatic surgery (33 standard resections, 6 limited resections). Fifteen patients had post-operative complications (morbidity 38.5%). The median DFS was 63 months, and 19 out of 36 patients showed a disease recurrence. The median OS was 134 months, and 13 out of 36 patients were alive with no evidence of disease. At univariate analysis, lymph node positivity (HR 5.1, 95% CI 1.5-18), multi-visceral resection (HR 3.4, 95% CI 1.1-10) and synchronous RCC-PMs (HR 13, 95% CI 3-55) were significantly associated with a short OS. CONCLUSION: Surgery may allow a DFS up to 17 years in more than one third of patients, even after limited resections. Splenectomy and lymph node dissection are not mandatory.

Serotonin-Secreting Neuroendocrine Tumours of the Pancreas.

BACKGROUND: Serotonin-secreting pancreatic neuroendocrine tumours (5-HT-secreting pNETs) are very rare, and characterised by high urinary 5-hydroxyindole-acetic acid (5-HIAA) levels (or high serum 5-HT levels). METHODS: Patients with 5-HT-secreting pancreatic neoplasms observed in our unit (1986-2015) were included. Diagnosis was based on urinary 5-HIAA or serum 5-HT levels. RESULTS: Seven patients were enrolled (4 M/3 F), with a median age of 64 (range 38-69) years. Two patients had a carcinoid syndrome. Serum 5-HT was elevated in four patients. Urinary 5-HIAA levels were positive in six patients. The median tumour size was 4.0 (range 2.5-10) cm. All patients showed liver metastases at diagnosis. None underwent resective surgery; lymph node/liver biopsies were taken. Six lesions were well-differentiated tumours and one a poorly differentiated carcinoma (Ki67 range 3.4-70%). All but one patient received chemotherapy. Four patients received somatostatin analogues; three patients underwent ablation of liver metastases. One patient is alive with disease 117 months after observation. All the others died from disease progression after a follow-up within 158 months. CONCLUSIONS: Primary 5-HT-secreting pNETs are mostly metastatic to the liver; patients are not amenable to resective surgery. Despite high 5-HIAA urinary levels, few patients present with carcinoid syndrome. A five-year survival rate of 42.9% may be achieved with multimodal treatment.

[Relapse surveillance of patients with testicular germ cell tumor]. / Surveillance des patients atteints de tumeur germinale du testicule.

Germ-cell tumors are the most common solid tumors in young men. The follow-up of these patients is very important in their management. In stage I testicular cancer, surveillance is the standard for low-risk disease. In addition to the early detection of relapse, follow-up should be directed towards prevention, detection and treatment of late toxicity, and secondary malignancies. Follow up consists in physical examination, laboratory analysis and radiological imaging. Recently, guidelines recommend risk-adapted surveillance strategy, with a reduction of CT scans numbers, due to the recognition of the risk of ionizing radiation exposure. However, efforts to maintain adequate compliance with follow up are required.

Audiometric Results of Stapedotomy Surgery for Otoscelorsis: Influence of the Radiological Stage.

BACKGROUND: The objective of this study was to identify a correlation between the radiological stage of otosclerosis and the pre- and postoperative audiometric results of patients who underwent a stapedotomy. METHODS: Ninety-three patients with radiologically and surgically confirmed otosclerosis who underwent stapedotomy surgery and CT scanning within 18 months before the operation were included. The CT scans were interpreted by an otologist and a specialised radiologist to determine their radiological stage according to the classification of Veillon and Fraysse. The patients received a pre- and postoperative audiogram in the short and long term. RESULTS: The preoperative bone conduction thresholds were higher in patients who presented with an advanced radiological stage of otosclerosis: 32.7 dB ±â€Š12.4 compared with those who presented with a less advanced radiological stage: 24.3 dB ±â€Š10.0. The preoperative air conduction thresholds were higher in patients who presented with an impairment of the round window: 58.1 dB ±â€Š13.5 compared with those who presented with no impairment of the round window: 48.7 dB ±â€Š14.5. The postoperative improvement in the air-bone gap was significantly higher for the localised foci: 16.9 dB ±â€Š8.6 versus 11.0 dB ±â€Š9.2, but only in the short term. CONCLUSION: There was a clinical radiological correlation with the preoperative results: In BC, there was a correlation with the radiological stage of Veillon and in AC, there was a correlation with impairment of the round window. The link between the radiological stage of otosclerosis and the postoperative audiometric results is less obvious. In the short term, the audiometric improvements in the air-bone gap were greater in patients in the early stages according to the Veillon classification, but this result was not sustained in the long-term.

Membrane proteinase 3 and its interactions within microdomains of neutrophil membranes.

Proteinase 3 (PR3) is a serine protease of neutrophil granules released to the medium or into the phagocytic vesicle upon neutrophil stimulation. A fraction of the enzyme is thought to associate with the cell membrane yielding membrane PR3 (mPR3). In autoimmune disorders characterized by the presence of antineutrophil cytoplasmic antibodies (ANCA), the reaction of the latter with their target antigen mPR3 activates the cell inflicting injuries on the surrounding tissues. In a previous communication we provided evidence for the presence of mPR3 in lipid rafts obtained by lysis of neutrophils in Triton X-100 and for the mediation of PR3 binding to the membrane by a glycosylphosphatidylinositol (GPI)-anchored neutrophil protein, possibly FcgammaRIIIb. In the current study we employed the mild detergent Brij 58 to isolate high molecular weight (HMW) protein complexes in the void volume of a Sepharose 4B gel filtration minicolumn. HMW complexes of unstimulated neutrophils comprised PR3, FcgammaRIIIb, the beta2 integrin CD11b/CD18 as well as the membrane and cytosolic subunits of the NADPH oxidase, p22phox and p47phox/p67phox. Treatment of neutrophils with phosphatidylinositol-specific phospholipase C (PI-PLC) reduced amounts of PR3 and FcgammaRIIIb in HMW complexes isolated from the treated cells, supporting our previous suggestion that FcgammaRIIIb acts as a membrane adaptor for PR3. FcgammaRIIIb of HMW fractions co-immunoprecipitated with PR3, indicating their presence in the same protein complex. Since HMW fractions contained also the majority of biotinylated proteins obtained by the reaction of neutrophils with a membrane impermeable biotinylating agent Sulfo-NHS-biotin, it was concluded that HMW proteins were derived from cell membranes. Lipid rafts isolated from Brij 58-lysed neutrophils were similar in their protein composition to the HMW complexes but not identical.

The presence of membrane Proteinase 3 in neutrophil lipid rafts and its colocalization with FcgammaRIIIb and cytochrome b558.

Proteinase 3 (PR3), the target autoantigen of antineutrophil cytoplasmic antibodies in the autoimmune vasculitis, Wegener's granulomatosis, is a serine proteinase stored in granules of human neutrophils. PR3 is expressed also on the plasma membrane of unactivated neutrophils, and this expression increases in primed or stimulated cells. In the current study, we demonstrate the presence of PR3, FcgammaRIIIb, and cytochrome b558 of the NADPH oxidase in neutrophil lipid rafts. Activation of neutrophils with PMA, fmet-leu-phe, or TNFalpha known to increase the membrane expression of PR3 did not affect the amount of PR3 in rafts. Unexpectedly, the cytosolic subunits of the NADPH oxidase, p67phox and p47phox, the recruitment of which to the membrane requires cell stimulation, were detected in the rafts of unstimulated neutrophils. Treatment of neutrophils with the cholesterol-sequestering agent methyl-beta-cyclodextrin (MbetaCD) reduced raft p22phox and PR3. MbetaCD diminished membrane FcgammaRIIIb upregulating membrane PR3 (mPR3) and CD11b/CD18. In addition, MbetaCD significantly reduced PMA-induced activity of the NADPH oxidase without altering fmet-leu-phe-elicited activity. Antibody-mediated cross-linking of membrane PR3 caused activation of ERK and JNK kinases and their translocation to rafts. Confocal analysis revealed colocalization of mPR3, FcgammaRIIIb, and p22phox in the membrane, confirmed by their coimmunoprecipitation. Cleavage of neutrophil GPI-anchors by PI-PLC reduced mPR3 and FcgammaRIIIb, implicating a GPI-protein, possibly FcgammaRIIIb, in the attachment of PR3 to the membrane.